Derivatives of acetic acid in compositions and methods for the alleviation of hyperlipemia

ABSTRACT

THIS DISCLOSURE RELATES TO DERIVATIVES OF ACETIC ACID, E.G., BIS(P-CHLOROPHENOXY)ACETIC ACID ISOPROPYL ESTER. THESECOMPOUNDS ARE USEFUL AS HYUPOCHOLESTEREMICS/HYPOLIPEMICS.

United States Patent 015cc n 3,660,579 Patented May 2, 1972 US. Cl.424308 22 Claims ABSTRACT OF THE DISCLOSURE This disclosure relates toderivatives of acetic acid, e.g., bis (p-chlorophenoxy)acetic acidisopropyl ester. Thesecompounds are useful ashypocholesteremics/hypolipemics.

This application is a division of Ser. No. 682,647, filed Nov. 13, 1967,which in turn is a continuation-in-part of application Ser. No. 560,874,filed June 27, 1966, now abandoned.

This invention relates to derivatives of acetic acid. In particular, theinvention pertains to bis-(aryloxy)acetic acids and alkyl esters thereofwhich possess hypocholesteremic/hypolipemic activity. The inventionfurther relates to pharmaceutical compositions containing the abovecompounds as an active ingredient thereof and the use of suchcompositions for the treatment of hypercholesteremic/ hypolipemia.

The compounds contemplated by the present invention are of thestructural formula R4 CHC O R wherein R represents H; or lower alkyl,straight or branched chain and preferably containing from 1 to 6 carbonatoms, e.g., methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyland hexyl; and each of R R R and R independently, represents H, chloro,bromo, or

iodo; provided at least one of R and R is other than H.

The preferred compounds of Formula I are those wherein both R, and R areother than H.

Those compounds of Formula I are known wherein R is H, methyl or ethyland either where (1) R and R are each chloro and R and R are H; or (2) RR R and R are each chloro ,(Chem. Abs. 61, 1793g). The present inventiononly contemplates the novel use of such compounds particularly ashypocholesteremic/hypolipemic agents. The other compounds encompassed byFormula I are new and also possess marked and unexpectedhypocholesteremic/hypolipemic activity.

The compounds of Formula I may be prepared according to severalprocesses. These processes may be classified generally into twodifierent categories, namely, (1) those which permit the obtaining ofbis-substituted phenoxy acetic acids and corresponding esters whereinthe substituents are the same on each of the two aromatic nuclei (i.e.,R =R R =R and (2) those whereby there may be obtained compounds withphenoxy groups having more than two different substituents thereon. Someof the processes fit into both categories. Various processes useful inpreparation of the acetic acids and corresponding esters of Formula Iare set out in the reaction flow chart below. As will be seen from thechart, processes F, G, J, K and L all provide the compounds of Formula Iwhere R is loweralkyl, whereas processes G, J, K and L provide the freeacids of Formula I. Processes A through F, inclusive, may be used toprovide bis-substituted phenoxy acetic acids having more than twodifferent types of substituents on (I) the aromatic nuclei.

R3 RI I I R,O 000R! cncoon o vrn 11 (IX) H 0001?.

COOR' halogenatlonl Nxcnzoooa' 010g halogenatlon COOR' R, R, n, I R,-omQ-on R, -o ooon' /CHCOOR' c n x (IV) 1: x \COOR' R4 COOR R4 1 R 0HXaCHCOOR x10 RP 0H COOR RB=R| Rl=R| n1 .1 R5=R4 (III) i i R -o n -o 1 .zo \i 1 l CHOOR 1'14 /C\ C OR ROH I g\\BOH or Alcoholate l a CHCOOH R4CHCOX (VII) (VI) R, R R R and R are as defined above, R represents loweralkyl, and X represents halo, preferably chloro or bromo.

Method F pertains to the reaction of a substituted phenoxy halo aceticacid ester (II) and an appropriately substituted phenol (III) as thephenolate. This reaction is conveniently elfected in a suitable inertorganic solvent such as dimethylacetamide; diethylacetamide;dimethylformamide; and tetramethylurea. Preferably, the reaction isinitially carried out at room temperature and then allowed to continueat elevated temperatures up to about 80 C. The particular solventemployed is not critical, nor is the temperature employed criticalprovided it does not exceed about 80 C. The resulting acetic acid ester(I) is readily recovered employing conventional techniques. Thesubstituted phenol (III) is readily converted to the phenolate usingstandard techniques, such as treating the phenol with either a strongalkali metal hydroxide, e.g., KOH or NaOH, and water or sodium hydridein dimethylacetamide.

Method G involves the reaction of the substituted phenol (IV) as aphenolate and a dihalocarboxylic acid ester or free acid and thesolvents and temperatures which may be used are substantially asdiscussed with respect to method F.

The process above identified as method J is conducted by treating anappropriately substituted malonic acid ester or free acid (V) with analcohol or alcoholate desirably in a suitable inert organic solvent,e.g., benzene, toluene and xylene, and in the presence of an alkalimetal alkoxide, such as methoxide and sodium ethoxide. The reaction isconveniently carried out at an elevated temperature, preferably thereflux temperature of the system. The resulting product (I) is readilyrecovered in a conventional manner.

Alternatively, the compounds of Formula I may be prepared according toprocess L above by reacting an appropriate bis-(substitutedphenoxy)acetyl halide (VI), such as the acetyl chloride, with anappropriate alcohol or alcoholate. The preparation of the acetylchloride (method M) and subsequent reaction thereof with alcohols areperformed according to methods described in the literature. When analcoholate is used instead of the free alcohol, it is generallypreferred to carry out the reaction in a suitable inert organic solventsuch as absolute diethyl ether. Such reaction is highly exothermic, andit is desirable to maintain the reaction temperature at about 30 C. Thisprocedure utilizing an alcoholate is particularly suitable for thepreparation of those compounds of Formula I wherein R is a tertiaryloweralkyl, e.g., t-butyl and t-pentyl.

The compound of Formula I may also be prepared according to process Kabove. This simple esterification may be carried out by treating thesubstituted bis-phenoxyacetic acids (VII) with an appropriate alcohol ina conventional manner. The esterification may be conducted at roomtemperature or at elevated temperatures. Preferably, it is conducted atreflux temperature and in the presence of a catalytic amount of hydrogenions such as may be supplied by the use of an arylsulfonic acid, e.g.,benzenesulfonic acid, p-toluenesulfonic acid and the like. The use of asolvent is not necessary since an excess of alcohol may be used for thatpurpose. The resulting product (I) is readily recovered in aconventional manner.

The substituted phenoxy haloacetic acid ester starting materials (II)used for process F described above may be prepared as indicatedaccording to processes D and E. Method D concerns treatment of thephenolate of compound (IV) with a monohaloacetic acid, e.g., chloroacetic acid, to obtain the substituted phenoxy acetic acid of FormulaVIII. The same solvents and reaction conditions discussed respectingprocesses F and G apply here as well. The compounds of Formula VIII arethen halogenated to provide the compounds of Formula II (method E).Conventional halogenating agents may be employed. The preferred agent isbromine or chlorine although other agents such as N-bromosuccinimide 0rsulfuryl chloride can also be used. The halogenation is convenientlycarried out in a suitable inert organic solvent such as halocarbon, forinstance a chloroalkane, e.g., dichloromethane, chloroform,carbontetrachloride, and the like. Preferably, the reaction is initiallycarried out at room temperature and then allowed to continue at refluxtemperature. However, neither the choice of solvent nor the temperatureused is critical.

The starting compounds of Formula V which are utilized in method J,discussed above, may be prepared by treating the phenolate of thecompound of Formula IV with dihalomalonic acid esters under the sameconditions and with the same solvents as described for the reaction ofthe dihaloacetic acid esters utilized in process G. The bis-(substitutedphenoxy)malonic acid esters of Formula V are also prepared by treatingphenolate of the compounds of Formula IV with a chloromalonic acid esterto provide the corresponding substituted malonic acid ester derivative(IX) (method A). The temperature and solvents used for method F may beutilized. The compounds of Formula IX are then halogenated (method B) ina manner as earlier discussed with respect to process E, and theresulting substituted phenoxy halomalonic acid ester (X) is treated witha phenolate of the compounds of Formula (III) (process C) to providestarting compounds (V) which is loweralkyl by utilizing the solvents andreaction conditions indicated hereinabove for process F.

Various of the phenolates and acetic acid and malonic acid derivativesemployed as reactants above are known and are prepared according tomethods disclosed in the literature. Those others not specificallydescribed in the literature are prepared by analogous methods from knownmaterials.

It should be understood that in each of processes G, H and I, it ispreferred that R represent lower alkyl since use of the free acid tendsto lower the yield of product (I).

As previously indicated, the compounds of Formula I are useful becausethey possess pharmacological properties in animals. In particular thesecompounds are useful as hypocholesteremics/hypolipemics, as indicated bytheir activity in sodium hexobarbital anesthetized rat tested byextracting serum or plasma with isopropanol and noting the chloesterolcontent. For such usage, the compounds may be administered orally assuch or admixed with conventional pharmaceutical carriers oradministered orally in such forms as tablets, dispersible powders,granules, capsules, syrups and elixirs. Such compositions may beprepared according to any method known in the art for the manufacture ofpharmaceutical compositions, and such compositions may contain one ormore conventional adjuvants, such as sweetening agents, flavoringagents, coloring agents and preserving agents, in order to provide anelegant and palatable preparation. Tablets may contain the activeingredient in admixture with conventional pharmaceutical excipients,e.g., inert diluents, such as calcium carbonate, sodium carbonate,lactose and talc, granulating and disintegrating agents, e.g., starchand aliginic acid, binding agents, e.g., starch, gelatin and acacia, andlubricating agents, e.g., magnesium stearate, stearic acid and talc. Thetablets may be uncoated or coated by known techniques to delaydisintegration and adsorption in the gastro-intestinal tract and therebyprovide a sustained action over a longer period. Similarly, suspensions,syrups and elixirs may contain the active ingredient in admixture withany of the conventional excipients utilized for the preparation of suchcompositions, e.g., suspending agents (methylcellulose, tragacanth andsodium alginate), wetting agents (lecithin, polyoxyethylene stearate andpolyoxyethylene sorbitan monooleate) and preservatives(ethyl-p-hydroxybenzoate). Capsules may contain the active ingredientsalone or admixed with an inert solid diluent, e.g., calcium carbonate,calcium phosphate and kaolin.

The compounds of Formula I where R=H may also be utilized ashypocholesteremics/hypolipemics in the form of non-toxicpharmaceutically acceptable salts thereof. As illustrative of such saltsthere may be included aluminum salt; non-toxic alkali metal salts, e.g.,potassium and sodium salts; non-toxic alkaline earth metal salts, e.g.,magnesium and calcium salts; salts with N-containing bases such asammonium salts and pharmaceutically acceptable primary, secondary andtertiary amine salts, e.g., ethanol amine salts, diethanol amine salts,and the like.

The dosage of active ingredient employed for the alleviation ofhyperlipemia (hypercholesteremia) may vary depending on the particularcompound employed and the severity of the condition being treated. Ingeneral, satisfactory results are obtained when these compounds areadministered at a daily dosage of from about .5 milligram to about 50milligrams per kilogram of animal body weight. This daily dosage ispreferably given in divided doses and administered 2-4 times a day, orin sustained release form. For most large mammals, the total dailydosage is from about 50-2000 mg, and dosage forms suitable for internaluse comprise from about 12.5 milligrams to about 500 milligrams ofactive compound in intimate admixture with a solid or liquidpharmaceutically acceptable carrier or diluent. The preferredpharmaceutical compositions from the standpoint of preparation and easeof administration are solid compositions, particularly hard-filledcapsules and tablets containing from 25 milligrams to about 250milligrams of the active ingredient.

The following examples serve to further illustrate the presentinvention. However, it is to be understood that the examples are forpurposes of illustration only and are not intended as in any waylimiting the scope of the invention which is defined in the appendedclaims. Furthermore, it is to be understood that the active ingredientused in Examples 6 and 7 can be replaced by any of the other known ornovel compounds described hereinabove and there are likewise obtainedpharmaceutical compositions suitable for the treatment of hyperlipemia.

EXAMPLE 1 Bis-(p-chlorophenoxy)acetic acid isopropyl ester H (o1o-)01100 0 011,

Bis-(p-chlorophenoxy)acetic acid, 40 gm., is refluxed for 14 hours in400 ml. of isopropanol containing 1.0 gm., of p-toluenesulfonic acid.The mixture is then cooled to about 60 C. and 3 gm. of potassiumcarbonate is added. The resulting mixture is then evaporated in vacuo,and the residue dissolved in 300 ml. of benzene. The benzene solution iswashed first with 100* ml. of water and then with 100 ml. of 10% aqueoussodium carbonate solution. The benzene is then evaporated in vacuo, andthe resulting crude product recrystallized from 150 ml. of isopropanoland washed with ice-cold petroleum ether to yieldbis-(p-chlorophenoxy)acetic acid isopropyl ester, M.P. 73.5-75 C.

EXAMPLE 2 Bis-(p-chlorophenoxy)acetic acid t-butyl ester (ClO-) CH0 0 OC(CHQ To a solution of 11.135 gm. of potassium t-butylate in ml. oft-butanol is added with stirring, while maintaining the reactiontemperature between 20 to 30 C., a solution of 33.2 gm. ofbis-(p-chlorophenoxy)acetyl chloride in 50 ml. of absolute diethylether. After the addition is completed, the mixture is stirred for anadditional 10 minutes and then evaporated in vacuo to dryness. To theresidue is added 200 ml. of chloroform, ml. of ice water and 10 ml. ofsaturated sodium bicarbonate solution. The organic phase is thenseparated, Washed with 75 ml. of water, dried over magnesium sulfate andevaporated. The crude product thus obtained is recrystallized fromcyclohexane and washed with ice-cold petroleum ether to yield bis(p-chlorophenoxy)acetic acid t-butyl ester, M.P. 92 C.

EXAMPLE 3 (p-Bromophenoxy) 2,4-dichlorophenoxy acetic acid methyl ester\CHCOOCH2 Step 1.(p-Bromophenoxy)-acetic acid methyl ester: Sodiumhydride (56.7% in mineral oil) (47 g.) is washed free from the mineraloil with low boiling petroleum ether and suspended in 750 ml. ofdimethylacetamide. To the suspension is added g. of p-bromophenol in 500ml. of dimethylacetamide as the temperature is maintained at 10-20 C.The mixture is stirred for two hours and methyl chloro acetate is added.The resulting mixture is stirred for five hours at 80 C. and then atroom temperature for 72 hours. The resulting mixture is then poured over2 liters of ice water, extracted with 750 ml. of isopropyl ether. Theorganic layer is separated, extracted with cold 1 N sodium hydroxide,dried over anhydrous sodium sulfate, filtered and evaporated to provide(p-bromophenoxy)-acetic acid methyl ester.

Step 2.u-Bromo-p-bromophenoxy acetic acid methyl ester: To 1 liter ofcarbon tetrachloride is added 180 g. of (p bromophenoxy)acetic acidmethyl ester. With stirring at room temperature bromine (160 g.) isadded dropwise and the mixture is stirred for 17 hours at roomtemperature. The mixture is washed with 1500 ml. of water and then 500ml. of cold 10% aqueous sodium bicarbonate. The organic layer isseparated, dried over anhydrous sodium sulfate and evaporated to providea-bromo-p-bromophenoxy acetic acid methyl ester.

Step 3.-(p-Bromophenoxy)-(2,4 dichlorophenoxy) acetic acid methyl ester:To 200 ml. of dimethylacetamide is added 15 g. of 2,4-dichlrophenol andthe resulting mixture is added dropwise, with stirring, to a suspensionof 4.6 g. of 56.7% sodium hydride (which had been washed free. ofmineral oil with petroleum ether) in 100 ml. of dimethylacetamide. Theresulting mixture is stirred at room temperature for 90 minutes and 26g. of a-bromo-p-bromophenoxy acetic acid methyl ester in 50 ml. ofdimethylacetamide is added in several portions. The mixture is stirredat room temperature for 72 hours, then at 50 C. for 30 minutes, pouredover 1500 ml. of ice water and extracted with 500 ml. of isopropylether.The ether layer is extracted with 100 ml. of cold 1 N sodium hydroxide,dried over anhydrous sodium sulfate, filtered and evaporated to yield(p-bromophenoxy)-(2,4 dichlorophenoxy) acetic acid methyl ester.

EXAMPLE 4 Bis(p-chlorophenoxy)acetic acid methyl ester (o1@-o-) CHO 00on,

When the procedure of Example 1 is repeated using methanol in place ofisopropanol, bis(p-chlorophenoxy) acetic acid methyl ester results. Whenthis procedure is repeated using different substituted acetic acids inplace of bis(p-chlorophenoxy)acetic acid, the following results areobtained:

Starting compound: Product Bis(p-iodophenoxy) ace- Bis(p iodophenoxy)acetic tic acid acid methyl ester (M.P.

105 C.) Bis (p bromophenoxy) Bis (p bromophenoxy)aceacetic acid tic acidmethyl ester (M.P. 75.580.5 C.).

EXAMPLE 5 Bis(p-bromophenoxy)acetic acid When the procedure of Example3, Step 1, is used and dichloroacetic acid is used in place ofmethylchloroacetate, there is obtained bis(p-bromophenoxy)acetic acid.

EXAMPLE 6 Tablets Tablets suitable for oral administration andcontaining the following ingredients are prepared by conventionaltabletting technique.

Ingredient: Weight (mg) Bis (p chlorophenoxy)acetic acid methyl ester250 Tragacanth 10 Lactose 197.5 Corn starch Talcum 15 Magnesium stearate2.5

The tablets so prepared are useful in the treatment ofhypercholesteremia at a dose of one tablet, 2 to 4 times a day.

8 EXAMPLE 7 Dry filled capsules Capsules suitable for oraladministration containing the following ingredients are prepared inconventional manner.

Ingredient: Weight (mg) Inert solid diluent (starch, lactose, or kaolin)250 Bis-(p-chlorophenoxy)acetic acid ethyl ester 250 E4 CHOOOR wherein 1I R represents alkyl having from 1 to 6 carbon atoms; and each of R R Rand R independently, represents a hydrogen atom, chloro, bromo or iodo,

provided that at least one of R and R is other than a hydrogen atom, anda solid orally administrable pharmaceutical carrier;

said compound being present in said composition in an amount suflicientto provide a daily dosage of from about 50 milligrams to about 200milligrams of said compound.

2. A composition of claim 1 wherein both R and R are other than hydrogenatoms.

3. A composition of claim 2 wherein the active ingredient isbis-(p-chlorophenoxy) acetic acid methyl ester.

4. A composition of claim 2 wherein the active ingredient isbis-(p-chlorophenoxy) acetic acid ethyl ester.

5. A composition of claim 2 wherein the active ingredient isbis-(p-bromophenoxy) acetic acid methyl ester.

6. A solid orally administrable pharmaceutical composition suitable foruse in the alleviation of hyperlipernia in mammals comprising as anactive ingredient thereof a compound of the formula:

CHCOOR wherein R represents alkyl having from 1 to 6 carbon atoms; andeach of R R R and R independently, represents a hydrogen atom, chloro,bromo or iodo,

provided that at least one of R and R is other than a hydrogen atom, anda solid orally administrable pharmaceutical carrier;

9. A composition of claim 7 wherein the active ingredient isbis-(p-chlorophenoxy) acetic acid ethyl ester.

10. A composition of claim 7 wherein the active ingredient is bis-(p-bromophenoxy) acetic acid methyl ester.

11. A method for the alleviation of hyperlipemia in a mammal whichcomprises orally administering to said mammal an effective amount of acompound of the formula:

CHCOOR wherein R represents alkyl having from 1 to 6 carbon atoms; andeach of R R R and R independently, represents a hydrogen atom, chloro,bromo r iodo,

provided that at least one of R and R is other than a hydrogen atom.

12. A method of claim 11 for the alleviation of hypercholesteremia in amammal.

13. A method of claim 12 wherein both R and R are hydrogen atoms.

14. A method of claim 13 wherein the compound is bis-(p-chlorophenoxy)acetic acid methyl ester.

15. A method of claim 13 wherein the compound is bis-(p-chlorophenoxy)acetic acid ethyl ester.

16. A method of claim 13 wherein the compound is bis-(p-bromophenoxy)acetic acid methyl ester.

17. A method for the alleviation of hyperlipemia in a mammal whichcomprises orally administering to said mammal a compound of the formula:

CHCOOR wherein R represents alkyl having from 1 to 6 carbon atoms; andeach of R R R and R independently, represents a hydrogen atom, chloro,bromo or iodo,

provided that at least one of R and R is other than a hydrogen atom,

References Cited Che-m. Abst. 61, 1793g (1964).

STANLEY J. FRIEDMAN, Primary Examiner US. Cl. X.R. 4243ll

